Optimization of the quinoline and substituted benzyl moieties of a series of phenyltetrazole leukotriene D4 receptor antagonists.

This report describes the development of a series of highly potent quinoline-based leukotriene D4 (LTD4) receptor antagonists containing an N-benzyl-substituted phenyltetrazole moiety. They were designed to provide both the correct positioning of the acidic function and secondary lipophilic domain required for strong receptor binding. Members of this series possess high activity in blocking LTD4-induced contractions of isolated guinea pig ileum. Compound 32, LY287192 (2-[[5-[3-[2-(7-chloroquinolin-2- yl)ethenyl]phenyl]-2H-tetrazol-2-yl]methyl]-5-fluorobenzoic acid sodium salt), blocked contraction with a pKB value of 9.1 +/- 0.3. Qualitative structure-activity studies have demonstrated specific requirements for the best activity. In particular, ortho substitution of the benzyl group with an acidic function was crucial for maximum potency. In cases similar to 32, where the benzyl group possesses an ortho carboxylate, the N-2-substituted tetrazole isomer showed 100-fold greater activity relative to the corresponding N-1 isomer. This pattern was reversed when the acid was substituted at the para position. The quinoline unit may be replaced by other nitrogen-containing heterocycles.     

Changes in the physiologic pattern of mitral prosthesis regurgitation in the presence of a prosthetic dysfunction]

AIM OF STUDY: Evaluation by transesophageal echocardiography of the effect on the characteristics of physiological regurgitant jets (JF) resulting from prosthetic disfunction due to pathologic regurgitation (JF). PATIENTS AND METHODS: We studied 69 consecutive patients with the diagnosis of prosthesis in mitral position using transesophageal echocardiography and color doppler codification. The patients were divided in two groups (N and D groups) according to the presence of prosthesis disfunction by pathologic regurgitation. In each patient we determined planimetric areas and atrial peak depth of each JF and also the sum of JF planimetric areas of each mitral prosthesis. When pathological regurgitation was present we calculated the highest planimetric area, severity degree and atrial peak depth in each JP. RESULTS: The planimetric area in each JF of group N was 330 +/- 167 mm2 and in group D 117 +/- 116 mm2 (p less than 0.001). The sum of the areas of JF in group N was 474 +/- 204 mm2 and in group D 254 +/- 176 mm2 (p less than 0.01). The atrial depth of JF in group was 32 +/- 15 mm and in group D 26 +/- 18 mm (p less than 0.01). In group D 29% of the patients had mild pathological regurgitation, 10% moderate and 61% severe. The maximum planimetric area of JP in group D was 1078 +/- 1007 mm2 with atrial depth of 37 +/- 28 mm. CONCLUSION: The pathological regurgitation in disfunction prosthesis in mitral position has a significant reduction effect in the dimension of prosthesis physiologic regurgitation jets. This transesophageal echocardiographic observation makes it possible to characterize and clarify more precisely the different types of mitral prosthesis jets.     

Sustained low-grade pro-inflammatory state in unmedicated, remitted women with major depressive disorder as evidenced by elevated serum levels of the acute phase proteins C-reactive protein and serum amyloid A.

BACKGROUND: Major depressive disorder (MDD) shows increased coronary artery disease (CAD) risk of unknown mechanism(s). MDD is more common in women than men; CAD diagnosis can be difficult in women. Elevations of the inflammatory markers C-reactive protein (CRP) and serum amyloid A (SAA) predict increased CAD risk in populations; few data on these markers exist in MDD, particularly in remitted patients. METHODS: We measured fasting am serum CRP (high sensitivity, CRP(hs)) and SAA in 18 unmedicated, remitted women with MDD (mean age 41 +/- (SD)12, body mass index (BMI) 25.2 +/- 4.1 kg/m(2)) and 18 BMI-matched healthy control subjects (age 36 +/- 10, BMI 25.3 +/- 3.8 kg/m(2)) on 2 separate occasions, > or = 6 days apart. RESULTS: Repeat SAA and CRP(hs) measurements strongly correlated across study days (SAA: r = .83, p < .001; CRP(hs): r = .94, p < .001). Both SAA (5.30 +/- 3.39 vs. 2.84 +/- 1.87 mg/L, p < .005) and CRP(hs) (3.23 +/- 3.17 vs. 1.12 +/- 1.45 mg/L; p < .01) were significantly elevated in MDD women versus controls. CONCLUSIONS: Elevated SAA and CRP(hs) in remitted, unmedicated women with MDD indicate a pro-inflammatory state unrelated to current depressive symptoms or pharmacotherapy. These findings suggest that inflammatory mechanisms may in part underlie findings of increased CAD risk in MDD.     

Avantage double mobility press--fit cup in total hip arthroplasty]

The Avantage double mobility press-fit cup was devised by Dr. Bousquet in the 70's to bring reasonable response to a problem of recurrent dislocation after total hip arthroplasty. The cup is attached to the femoral head by a bipolar polyethylene liner. The polyethylene liner moves freely inside a shiny--polished metal cup. The angular range of motion before impingement is increased by the mobility of the liner. The double connection (cup-liner, liner-head) reduces the stress on the metal cup and improve the stability of the prosthesis. The solution has proved to be efficient in reducing dislocation risk and maintains at the same time the appropriate range of motion. Between January 2004 and November 2005, 113 hip arthroplasties in 108 women with use of the double mobility cup were performed. The cemented version of the Avantage cup was inserted in 15 patients (mean age--76.9 years). Uncemented, HA coated implant was used in 98 patients (with mean age of 55 years). The mean follow-up was 20.4 months. No one patient was lost to follow-up. No postoperative dislocation was observed during follow-up. There was no unwanted leg lengthening greater than 1 cm. The Avantage cup may be indicated in any primary total hip arthroplasty especially in those with increased risk of postoperative dislocations. This cup enables a correct balance of the hip without a need of the unwanted lengthening of the leg.     

Long-term results of treatment for articular calcaneus fractures with Westhues method]

In this paper the authors evaluate the long-term results of treatment for articular calcaneus fractures with Westhues method. This evaluation is performed with regard to triple measurement of B?hler's angle value and to subjective criteria. The clinical material from years 1985-2002 consists of 47 patients aged between 24 and 56 years (mean age 32 years) with articular calcaneus fractures--namely, 41 male patients (87.2%) and 6 female patients (12.8%). The follow-up examination was performed in 24 patients (51% of all patients), namely, in 23 male patients (48.8%) and in one female patient (2.2%). Minimum follow-up time was 12 months and maximum was 9 years. Acquired results suggest that Westhues method restores normal B?hler's angle value only in tongue-type calcaneous fractures.     

Application of the Minnesota Code in evaluating electrocardiographic features of ischemic heart disease in patients exposed to carbon disulphide

Summary We examined 81 men exposed for a long time to carbon disulphide (CS₂) and tested the possible electrocardiographic (ECG) changes of ischemic heart disease (I.H.D.). The subjects were examined twice in two years. In order to make the ECG evaluation more objective, the Minnesota Code was applied. Two obligatory ECG examinations and only one submaximal effort test were carried out. For comparative evaluation, the control group was examined once. We proved that, in spite of the accepted opinion concerning the atheromatous action of CS₂, this compound does not cause ECG symptoms of I.H.D. in a higher percentage of exposed persons. It also does not cause any significant increase in I.H.D. symptoms in dynamic ECG observations.